Amyotrophic Lateral Sclerosis/motor Neuron Disease Research Articles

Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates

Objective: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12. Methods: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories. Results: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King’s stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01). Conclusion: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.

Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change

Background The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items. Method Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling. Results No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale. Conclusion A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials.

Psychosocial interventions for people with amyotrophic lateral sclerosis and motor neuron disease and their caregivers: a scoping review

BackgroundAs amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) is a fatal progressive neurodegenerative disorder, patients experience severe impairments, with patients and family caregivers facing emotional distress and exhaustion. Several psychosocial interventions are aimed at providing tailored support for ALS/MND patients and caregivers. The aim of this study was to conduct a scoping review and present a comprehensive overview of psychosocial interventions designed for individuals and families affected by ALS/MND, while also pinpointing research gaps.MethodsThis scoping review utilized Arksey and O'Malley's methodological framework to investigate psychosocial interventions designed for individuals with ALS/MND and their families. The study adhered to the PRISMA-ScR checklist for reporting.ResultsA total of 27 articles describing 25 interventions met the inclusion criteria. The predominant interventions observed in the research encompassed education-related strategies, closely followed by behavior therapy, counseling, social support interventions, and psychotherapy interventions. Across the majority of the studies, findings indicated promising feasibility and acceptability of these interventions. Notably, a significant proportion of quantitative investigations yielded one or more statistically significant effects, while qualitative studies consistently reported favorable outcomes, including enhancements in well-being and heightened awareness of individual circumstances.ConclusionsGiven the progressive and debilitating nature of this condition, coupled with the absence of a cure, the adoption of a psychosocial approach can prove beneficial for both ALS/MND patients and their families. However, high-quality RCTs with a large sample size are recommended to examine and confirm the effectiveness.

Amyotrophic lateral sclerosis-Motor neuron disease with a wide clinical and genetic spectrum

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Besides a timely diagnosis, precise knowledge of the clinical manifestations and differential diagnoses is essential. While most patients develop the disease at an older age, hereditary causes play amore frequent role in the juvenile forms. What is the current state of ALS diagnostics, which new treatment options exist? Literature search using Pubmed.gov. The main focus is on an individualized symptomatic treatment as no curative treatment approaches exist. However, new insights into the genetic and pathophysiological principles of the different forms of ALS open the way for future disease-modifying treatment options. In cases of a clinical suspicion of ALS molecular genetic diagnostics should be considered, particularly in juvenile and young adult patients, to exclude differential diagnoses and to enable patients access to new treatment approaches.

Diaphragmatic ultrasound: Prospects as a tool to assess respiratory muscle involvement in amyotrophic lateral sclerosis.

Ultrasonography (USG) of the diaphragm is a promising alternative to pulmonary function tests (PFT) for assessing respiratory function in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We studied 33 patients fulfilling Awaji criteria (definite=14; probable=12; possible=7) and 33 age and gender-matched controls. Diaphragm thickness was measured using USG at the end of expiration (DTex) and end of inspiration (DTin). The thickness ratio (TR) was calculated as DTin/DTex. The mean age at onset and duration were 49.73 ± 12.7 years and 13.57 ± 9.7months, respectively. Men=25 (75.8%); Limb onset ALS/MND=24 patients (72.7%); bulbar onset=9 (27.3%). Compared to controls, ALS/MND patients had reduced mean DTex (2.22 ± 0.29 mm vs. 2.02 ± 0.32 mm, p=.012) and DTin (4.0 ± 0.71 mm vs. 3.41 ± 0.38 mm, p < .001). PFTs done in 31 patients showed restrictive abnormality in 80.6%. Significant positive correlation was seen between percentage of predicted forced vital capacity (FVC%) and DTin (p=.009) and TR (p=.037) but not with DTex (p=.852). No significant correlation was seen between diaphragmatic thickness and other PFT parameters or ALSFRS scores. The diaphragmatic thickness showed a significant decrease in ALS/MND as compared to controls. End-inspiratory diaphragmatic thickness and TR correlated well with %FVC. Thus, diaphragmatic USG could be a potential alternative to PFTs in assessing respiratory function in ALS/MND patients having the advantage of less patient participation and ease of performing in late stages of ALS/MND.

Strategy for screening cognitive impairment in Chinese patients with amyotrophic lateral sclerosis

BackgroundIt is an economical strategy to design a screening method to decide which patients with amyotrophic lateral sclerosis/ motor neuron disease (ALS/MND) should enter into the stage for further comprehensive neuropsychological investigation. Methods59 patients (including 8 with frank dementia) were recruited. They underwent the extensive neuropsychological evaluation and short screening batteries, namely the Mini-Mental State Examination (MMSE), the Peking Union Medical College Hospital version of Montreal Cognitive Assessment (MoCA-P) and the Frontal Assessment Battery (FAB). Results of the extensive neuropsychological evaluation were set as the gold standard to diagnose cognitive impairment, and the effectiveness of screening tests were measured against them. ResultsBy comparing the sensitivity and specificity, we found that the combination of FAB plus both or either of the other 2 short batteries provided a satisfactorily high sensitivity, but none of these screening batteries was significantly associated with quantitative behavioral measurements among non-demented subjects, the Frontal Behavioral Inventory-ALS version (FBI-ALS). ConclusionsThe combination of the FBI-ALS, the FAB, and the MMSE or the MoCA-P or both could effectively screen comorbid dementia, cognitive and behavioral impairment in ALS but this implicates a limited specificity. And the FAB needed to be validated in large Chinese sample.

An miRNA fingerprint using neural-enriched extracellular vesicles from blood plasma: towards a biomarker for amyotrophic lateral sclerosis/motor neuron disease

Biomarkers for amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are currently not clinically available for disease diagnosis or analysis of disease progression. If identified, biomarkers could improve patient outcomes by enabling early intervention and assist in the determination of treatment efficacy. We hypothesized that neural-enriched extracellular vesicles could provide microRNA (miRNA) fingerprints with unequivocal signatures of neurodegeneration. Using blood plasma from ALS/MND patients and controls, we extracted neural-enriched extracellular vesicle fractions and conducted next-generation sequencing and qPCR of miRNA components of the transcriptome. We here report eight miRNA sequences which significantly distinguish ALS/MND patients from controls in a replicated experiment using a second cohort of patients and controls. miRNA sequences from patient blood samples using neural-enriched extracellular vesicles may yield unique insights into mechanisms of neurodegeneration and assist in early diagnosis of ALS/MND.

L-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND.

The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin β-N-methylamino-l-alanine (BMAA). We report here the occurrence of ALS/MND-type pathological changes in vervets (Chlorocebus sabaeus; n = 8) fed oral doses of a dry powder of BMAA HCl salt (210 mg/kg/day) for 140 days. Spinal cords and brains from toxin-exposed vervets were compared to controls fed rice flour (210 mg/kg/day) and to vervets coadministered equal amounts of BMAA and l-serine (210 mg/kg/day). Immunohistochemistry and quantitative image analysis were used to examine markers of ALS/MND and glial activation. UHPLC-MS/MS was used to confirm BMAA exposures in dosed vervets. Motor neuron degeneration was demonstrated in BMAA-dosed vervets by TDP-43+ proteinopathy in anterior horn cells, by reactive astrogliosis, by activated microglia, and by damage to myelinated axons in the lateral corticospinal tracts. Vervets dosed with BMAA + l-serine displayed reduced neuropathological changes. This study demonstrates that chronic dietary exposure to BMAA causes ALS/MND-type pathological changes in the vervet and coadministration of l-serine reduces the amount of reactive gliosis and the number of protein inclusions in motor neurons.

Clinical and prognostic features of ALS/MND in different phenotypes–data from a hospital-based registry

ObjectivesTo explore the natural history, clinical features, and survival relevance of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) with different phenotypes. MethodsAll patients were prospectively enrolled in a hospital-based register from 2006 to 2015. Cases were classified according to established phenotypes: classic, bulbar, flail arm, flail leg, upper motor neuron dominate, respiratory, pure lower motor neuron and pure upper motor neuron. Survival was analyzed using Kaplan-Meier curves and Cox regression analysis. ResultsA total of 1157 patients with complete clinical information were registered in the current cohort study. The classic phenotype was the most frequent phenotype. The mean age of onset, diagnostic delay, smoking status, exposure to pesticides and mean survival time were significantly different among different phenotypes. The median survival time was 3.1 years for all patients. At the end of the analysis, the 3-year survival rate was 62.1%, the 5-year survival rate was 39.6%, and the 10-year survival rate was 22.0%. The Cox analysis revealed that the disease phenotype was an independent predictor of survival (hazard ratio = 0.825, P < 0.001), after adjusting for other factors. ConclusionsThis study showed the natural history data of ALS/MND and supported the theory that varied disease phenotypes had different clinical, demographic and prognostic characteristics, which provided the basis for analysis of future management and treatment for ALS/MND. Furthermore, the phenotypic expression of ALS/MND with distinctive characteristics is important for providing complementary information for identifying the underlying mechanisms of the diseases.

TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics

Transactive response DNA-binding protein of 43 kDa (TDP-43) functions as a heterogeneous nuclear ribonucleoprotein and is the major pathological protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). TDP-43 pathology may also be present as a comorbidity in approximately 20–50% of sporadic Alzheimer’s disease cases. In a mouse model of MND, full-length TDP-43 increases association with the mitochondria and blocking the TDP-43/mitochondria interaction ameliorates motor dysfunction. Utilizing a proteomics screen, several mitochondrial TDP-43-interacting partners were identified, including voltage-gated anion channel 1 (VDAC1) and prohibitin 2 (PHB2), a crucial mitophagy receptor. Overexpression of TDP-43 led to an increase in PHB2 whereas TDP-43 knockdown reduced PHB2 expression in cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inducer of mitophagy. These results suggest that TDP-43 expression contributes to metabolism and mitochondrial function however we show no change in bioenergetics when TDP-43 is overexpressed and knocked down in HEK293T cells. Furthermore, the fusion protein mitofusin 2 (MFN2) interacts in complex with TDP-43 and selective expression of human TDP-43 in the hippocampus and cortex induced an age-dependent change in Mfn2 expression. Mitochondria morphology is altered in 9-month-old mice selectively expressing TDP-43 in an APP/PS1 background compared with APP/PS1 littermates. We further confirmed TDP-43 localization to the mitochondria using immunogold labeled TDP-43 transmission electron microscopy (TEM) and mitochondrial isolation methods There was no increase in full-length TDP-43 localized to the mitochondria in APP/PS1 mice compared to wild-type (littermates); however, using C- and N-terminal-specific TDP-43 antibodies, the N-terminal (27 kDa, N27) and C-terminal (30 kDa, C30) fragments of TDP-43 are greatly enriched in mitochondrial fractions. In addition, when the mitochondrial peptidase (PMPCA) is overexpressed there is an increase in the N-terminal fragment (N27). These results suggest that TDP-43 processing may contribute to metabolism and mitochondrial function.

Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS).

We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), DAOR199W, associated with familial Amyotrophic Lateral Sclerosis (ALS) that impairs D-serine metabolism and causes protein aggregation, autophagy and cell death in motor neuron cell lines. These features are consistent with the pathogenic processes occurring in ALS but most importantly, we have demonstrated that activation of the formation of ubiquitinated protein inclusions, increased autophagosome production and apoptotic cell death caused by the mutation in cell lines are attenuated by 5,7-dichlorokynurenic acid (DCKA), a selective inhibitor of the glycine/D-serine binding site of the NMDA receptor. D-serine is an essential co-agonist at this glutamate receptor. This data provides insight into potential upstream mechanisms that involve the action of D-serine at the NMDA receptor and might contribute to neurodegeneration. This is highly relevant to sporadic ALS (SALS), familial ALS, as well as ALS models, where elevated levels of D-serine have been reported and hence has broader clinical therapeutic implications. In order to investigate this further, we have generated a transgenic line expressing the pathogenic mutation, in order to determine whether mice expressing DAOR199W develop a motor phenotype and whether crossing the SOD1G93A model of ALS with mice expressing DAOR199W affects disease progression. We found that heterozygous expression of DAOR199W led to a significant loss of spinal cord motor neurons at 14 months, which is similar to that found in homozygous mice expressing DAOG181R. We hypothesize that DAO has potential for development as a therapeutic agent in ALS.

Age-Related Uptake of Heavy Metals in Human Spinal Interneurons.

Toxic heavy metals have been implicated in the loss of spinal motoneurons in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Motoneuron loss in the spinal anterior horn is severe in ALS/MND at the time of death, making this tissue unsuitable for examination. We therefore examined spinal cords of people without muscle weakness to look for any presence of heavy metals that could make these neurons susceptible to damage. Spinal cord samples from 50 individuals aged 1–95 y who had no clinical or histopathological evidence of spinal motoneuron loss were studied. Seven μm formalin-fixed paraffin-embedded sections were stained for heavy metals with silver nitrate autometallography (AMGHM) which detects intracellular mercury, silver or bismuth. Neurons in the spinal cord were classified as interneurons or α-motoneurons based on their site and cell body diameter. Spinal interneurons containing heavy metals were present in 8 of 24 people (33%) aged 61–95 y, but not at younger ages. These AMGHM interneurons were most numerous in the lumbar spinal cord, with moderate numbers in the caudal cervical cord, few in the rostral cervical cord, and almost none in the thoracic cord. All people with AMGHM interneurons had occasional AMGHM staining in α-motoneurons as well. In one man AMGHM staining was present in addition in dorsomedial nucleus and sensory neurons. In conclusion, heavy metals are present in many spinal interneurons, and in a few α-motoneurons, in a large proportion of older people. Damage to inhibitory interneurons from toxic metals in later life could result in excitotoxic injury to motoneurons and may underlie motoneuron injury or loss in conditions such as ALS/MND, multiple sclerosis, sarcopenia and calf fasciculations.

Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort.

ObjectiveTo capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia.MethodsData were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death.DesignProspective observational cohort study.Participants1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015.Results5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p<0.004). There were delays in the median time to diagnosis of up to 12 months for the ALS phenotypes, 18 months for the flail limb phenotypes and 19 months for PLS. Riluzole treatment was started in 78–85% of cases. The median delays in initiating riluzole therapy, from symptom onset, varied from 10 to 12 months in the ALS phenotypes and 15–18 months in the flail limb phenotypes. Percutaneous endoscopic gastrostomy was implemented in 8–36% of ALS phenotypes and 2–9% of the flail phenotypes. Non-invasive ventilation was started in 16–22% of ALS phenotypes and 21–29% of flail phenotypes.ConclusionsThe establishment of a cohort registry for ALS/MND is able to determine clinical phenotypes, survival and monitor time to key milestones in disease progression. It is intended to expand the cohort to a more population-based registry using opt-out methodology and facilitate data linkage to other national registries.

Frequency and risk factor analysis of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease.

ObjectivesTo examine the frequency and risk factors of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND).MethodsThis was an observational study of 100 ALS/MND patients treated at our hospital outpatient and inpatient departments between January 2009 and April 2010 and 100 matched healthy controls. Subjects were surveyed using Mini Mental State Examination (MMSE), Zung Self-Rating Anxiety Scale (SAS), and Zung Self-Rating Depression Scale (SDS). Patient neurological status was graded by the ALS Functional Rating Scale (ALSFRS). Multivariate linear regression was used to identify factors associated with the MMSE, SAS, SDS, and ALSFRS scores.ResultsPatients had significantly lower MMSE scores than controls (P<0.05). MMSE score did not differ by sex or age (<50/≥50 years) (P>0.05). Patients with higher educational level (college and above), shorter disease course (<2 years), and lower ALSFRS score (<20) had significantly higher MMSE scores (all P<0.05). Multivariate analysis revealed that higher education, shorter disease course, and lower ALSFRS score were independent predictors of better cognitive function (higher MMSE score). Patients had significantly higher mean SAS and SDS total scores than controls (both P<0.05), indicating higher subjective anxiety and depression. Female patients, patients with higher education, and those with higher ALSFRS scores had significantly higher SAS and SDS scores (all P<0.05). Age, occupation, diagnostic classification, disease duration, and disease awareness did not influence SAS or SDS scores. Multivariate analysis indicated that lower education and lower ALSFRS were protective factors against anxiety and depression.ConclusionThe frequency of anxiety-depressive disorders was high among patients with ALS/MND. High educational level, short course of disease, and lower ALSFRS were associated with preserved cognitive function. Female sex, higher education, and lower ALSFRS score conferred a greater risk of anxiety and depression. Tailored pharmacotherapy and psychological interventions may help in reducing anxiety and depression in these patients.

Behavioral Symptoms in Motor Neuron Disease and Their Negative Impact on Caregiver Burden.

Background:The spectrum of abnormal behaviors in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been described, but its practical meaning, namely its impact on caregiver burden, has not been clearly documented in Chinese population. This study aimed to assess the distribution of abnormal behaviors in Chinese population, and to analyze the relationship between behavior changes and caregiver burden.Methods:Sixty-five patients with ALS/MND have been consecutively enrolled into registry platform of Peking Union Medical College Hospital. An investigation was performed to these patients and their caregivers using the revised ALS function rating scale, Frontal Behavioral Inventory-ALS version, the Frontal Assessment Battery, and the Caregiver Burden Inventory.Results:Twenty-eight (43.1%) patients displayed abnormal behaviors of varying degrees, with one fulfilling the diagnostic criteria of frontotemporal lobe degeneration. Irritability, logopenia, and inflexibility ranked top 3 of abnormal behavior list. Correlation analysis revealed that the degree of behavioral change and frontal cognitive status were significantly associated with caregiver burden, with more extensive impact from disinhibitive behaviors. Analysis of covariance analysis showed that after associated factors were corrected, caregivers of patients with moderate to severe behavior change reported significantly heavier developmental burden, physical burden, and total burden than those with no behavioral change.Conclusions:Neurobehavioral symptoms could present in around 40% of Chinese patients with ALS/MND, and the distribution of these behaviors was also unique. Besides, abnormal behaviors were highly related to caregivers’ burden.

Spirituality and/or religious faith: A means for coping with the effects of amyotrophic lateral sclerosis/motor neuron disease?

The notion of spirituality/religious belief is recognized internationally as a domain within end-of-life care and is important in patients' and carers' quality-of-life. When faced with incurable illness, patients often become more philosophical about their life; many seek comfort in spiritual or religious philosophies. Our intention was to understand how personal spirituality and religious faith might help those living with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) cope with their impending death. Unsolicited narratives (internet and print-published) written by individuals diagnosed with the terminal condition of ALS/MND were analyzed thematically. Narratives from 161 individuals diagnosed with ALS/MND written over a period of 37 years (from 1968 to 2005) were included. Our findings reveal that religious faith sustains and helps people to avoid despair, and personal spirituality helps them make sense of what is happening to them. The use of personal narratives by people with ALS/MND has provided a vehicle for sharing their deepest spiritual and religious thoughts with others. The place of spirituality and religious faith within ALS/MND care should not be underestimated. Assessment of religious or spiritual needs should become a routine part of practice and is the responsibility of all members of the multidisciplinary team.

Treatment for fatigue in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND)

Treatment for fatigue in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND)

Handwriting-in-interaction Between People with ALS/MND and their Conversation Partners

The aim of this study was to examine the use and practices of handwriting-in-interaction by people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Handwriting has previously been described as a viable and practical means of augmentative and alternative communication, particularly for adults with acquired progressive dysarthria and intact upper limb control. To date, however, there is extremely limited evidence documenting how handwriting is used within a conversational context. The analysis in this paper features data from two people with ALS/MND in conversation at home with their spouses. It is shown how recipient animation of an authored written contribution is an important element of handwriting-in-interaction, particularly in how the recipient reveals his or her stance or reaction to whatever has been written.

Diaphragm pacing and noninvasive respiratory management of amyotrophic lateral sclerosis/motor neuron disease

Although it is known that continuous noninvasive ventilation (CNIV) can prolong life in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), in this study we explore similar claims for diaphragm pacing (DP). NIV and DP users' vital capacities (VCs) over time and duration of NIV and CNIV dependence were analyzed for 354 non-DP and 8 DP ALS/MND patients. Patients had a higher rate of monthly VC decline before NIV use (5.1 ± 7.6%) than during NIV use (2.5 ± 3.6%) (P < 0.01, 95% CI 0.84-4.5); the decline for 4 DP users was 3.7-20%. Fifty-five ALS/MND patients used part-time NIV for 19.9 ± 27.6 months until tracheostomy/death, whereas 113 others used it for 10.9 ± 10.5 months until CNIV dependence for another 12.8 ± 16.2 months. After placement, 7 DP users were CNIV dependent in 8.0 ± 7.0 months, whereas 6 underwent tracheostomy/died in 18.2 ± 13.7 months. CNIV prolonged the survival of 113 of the 354 non-DP and 6 DP ALS/MND patients by 12.8 and 10.2 months, respectively. DP provided no benefit on VC or mechanical ventilation-free survival.

Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease

Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials. To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND. We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information. We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy. All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction. Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small studies showed a statistically nonsignificant result for the amino acid L-threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps. There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.